HIGHLIGHTS OF PRESCRIBING INFORMATION |
These highlights do not include all the information needed to use tykerb safely and effectively. See full prescribing information for tykerb. |
tykerb (lapatinib) tablet for oral use
Initial U.S. Approval: 2007
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WARNING:
HEPATOTOXICITY
See full prescribing information for complete boxed warning.
Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).]
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RECENT MAJOR CHANGES
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Boxed Warning.
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July 2008
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Hepatotoxicity. (5.2, 17.6)
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July 2008
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Interstitial lung disease and pneumonitis. (5.5)
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August 2007
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INDICATIONS AND USAGE
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TYKERB®, a kinase inhibitor, is indicated in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. (1)
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DOSAGE AND ADMINISTRATION
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The recommended dosage of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. (2.1)
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TYKERB should be taken at least one hour before or one hour after a meal. However, capecitabine should be taken with food or within 30 minutes after food. (2.1)
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TYKERB should be taken once daily. Do not divide daily doses of TYKERB. (2.1, 12.3)
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Modify dose for cardiac and other toxicities, severe hepatic impairment, and CYP3A4 drug interactions. (2.2)
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DOSAGE FORMS AND STRENGTHS
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250 mg tablets (3)
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CONTRAINDICATIONS
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None. (4)
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WARNINGS AND PRECAUTIONS
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Decreases in left ventricular ejection fraction have been reported. Confirm normal LVEF before starting TYKERB and continue eva luations during treatment. (5.1)
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Lapatinib has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. Discontinue and do not restart TYKERB if patients experience severe changes in liver function tests. (5.2)
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Dose reduction in patients with severe hepatic impairment should be considered. (2.2, 5.3, 8.7)
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Diarrhea, including severe diarrhea, has been reported during treatment. Manage with anti-diarrheal agents, and replace fluids and electrolytes if severe. (5.4)
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Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue TYKERB if patients experience severe pulmonary symptoms. (5.5)
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Lapatinib prolongs the QT interval in some patients. Consider ECG and electrolyte monitoring. (5.6)
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Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. (5.7)
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ADVERSE REACTIONS
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The most common (>20%) adverse reactions during treatment with TYKERB plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue. (6.1)
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To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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DRUG INTERACTIONS
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TYKERB is likely to increase exposure to concomitantly administered drugs which are metabolized by CYP3A4 or CYP2C8. (7.1)
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Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2)
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Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of TYKERB in patients coadministered a strong CYP3A4 inducer. (2.2, 7.2)
Revised: July 2008
TKB:4PI
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See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling |
Revised: 07/2008 |
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FULL PRESCRIBING INFORMATION: CONTENTS* |
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FULL PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY
Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).]
1 INDICATIONS AND USAGE
TYKERB is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The recommended dose of TYKERB is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)]. Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.
2.2 Dose Modification Guidelines
Cardiac Events
TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. TYKERB may be restarted at a reduced dose (1,000 mg/day) after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic.
Hepatic Impairment
Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of TYKERB reduced. A dose reduction to 750 mg/day in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there is no clinical data with this dose adjustment in patients with severe hepatic impairment.
Concomitant Strong CYP3A4 Inhibitors
The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).]
Concomitant Strong CYP3A4 Inducers
The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2).]
Other Toxicities
Discontinuation or interruption of dosing with TYKERB may be considered when patients develop ≥Grade 2 NCI CTC toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB should be restarted at a lower dose (1,000 mg/day).
See manufacturer’s prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity.
3 DOSAGE FORMS AND STRENGTHS
250 mg tablets — oval, biconvex, orange, film-coated with GS XJG debossed on one side.
4 CONTRAINDICATIONS
None.
See manufacturer’s prescribing information for capecitabine contraindications.
5 WARNINGS AND PRECAUTIONS
5.1 Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if TYKERB is to be administered to patients with conditions that could impair left ventricular function. LVEF should be eva luated in all patients prior to initiation of treatment with TYKERB to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be eva luated during treatment with TYKERB to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)].
5.2 Hepatotoxicity
Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be retreated with TYKERB [see Adverse Reactions (6.1)].
5.3 Patients with Severe Hepatic Impairment
If TYKERB is to be administered to patients with severe pre-existing hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Warnings and Precautions (5.2)].
5.4 Diarrhea
Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.
5.5 Interstitial Lung Disease/Pneumonitis
Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1)]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).
5.6 QT Prolongation
QT prolongation measured by automated machine-read eva luation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4)]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration. The prescriber should consider baseline and on-treatment electrocardiograms with QT measurement.
5.7 Pregnancy
Pregnancy Category D
TYKERB can cause fetal harm when administered to a pregnant woman. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC).
Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
There are no adequate and well-controlled studies with TYKERB in pregnant women. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
The safety of TYKERB has been eva luated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was eva luated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies (14).] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.
The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodyse